Overview
Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Defective CFTR function results in abnormal chloride and bicarbonate transport across epithelial surfaces, producing thick, viscous secretions that impair mucociliary clearance and exocrine gland function. The disease primarily affects the respiratory, gastrointestinal, and reproductive systems and increasingly requires life‑long, multidisciplinary care into adulthood.
Epidemiology
CF incidence varies by ancestry: approximately 1 in 2,500 live births in Caucasian populations, ~1 in 17,000 in Black populations, and considerably rarer in many Asian populations. Advances in newborn screening, antibiotics, airway clearance, and CFTR modulators have substantially improved survival; median survival now extends into the fourth decade and beyond in many high‑income settings.
Genetics and Pathophysiology
CFTR is located on chromosome 7. Over 1,000 CFTR variants are reported; the ΔF508 (Phe508del) deletion is the most common pathogenic variant and causes defective protein folding and trafficking. CFTR variants are grouped by mechanism (e.g., synthesis, processing, gating, conductance, quantity). Loss of CFTR chloride/bicarbonate transport leads to dehydrated airway surface liquid, impaired mucociliary clearance, and a cycle of airway obstruction, infection, neutrophilic inflammation, and structural lung damage (bronchiectasis, bronchial wall destruction). Pancreatic exocrine insufficiency results from plug formation in pancreatic ducts, causing malabsorption and failure to thrive; endocrine dysfunction can progress to cystic fibrosis–related diabetes (CFRD).
Clinical Presentation
Presentation varies by age and genotype. Common features include:
- Respiratory: chronic productive cough, recurrent lower respiratory tract infections (Pseudomonas aeruginosa, Staphylococcus aureus, Burkholderia cepacia complex), bronchiectasis, digital clubbing, hemoptysis, and progressive decline in FEV1.
- Gastrointestinal: meconium ileus in neonates, failure to thrive, steatorrhea from fat malabsorption, hepatobiliary disease, and distal intestinal obstruction syndrome (DIOS).
- ENT and sinus disease: chronic rhinosinusitis and nasal polyposis.
- Reproductive: congenital bilateral absence of the vas deferens (CBAVD) causing obstructive azoospermia in most males; variable effects on female fertility.
- Other: electrolyte abnormalities (e.g., hyponatremic dehydration in hot climates), fat‑soluble vitamin deficiency, and CFRD.
Diagnosis
Confirmatory testing is indicated for infants with positive newborn screens or patients with clinical features suggestive of CF.
- Sweat chloride test: Gold standard functional test; values ≥60 mmol/L are diagnostic in most labs, 30–59 mmol/L indeterminate (age-dependent), and <30 mmol/L usually normal in older children/adults (thresholds may vary by lab and age).
- Genetic testing: CFTR mutation panel or full gene sequencing to identify pathogenic variants; informs prognosis and eligibility for CFTR modulator therapy.
- Additional assessments: Baseline chest radiography/CT, pulmonary function testing, sputum microbiology, stool elastase for pancreatic insufficiency, liver function tests, and screening for CFRD (OGTT in adolescents/adults or annual fasting glucose/A1c as recommended).
Management Principles
Management is multidisciplinary and personalized to genotype, age, and disease severity.
- Airway clearance: Daily airway clearance techniques (ACTs), percussion, positive expiratory pressure (PEP) devices, oscillatory vests, and individualized chest physiotherapy.
- Inhaled therapies: Nebulized hypertonic saline (improves mucus clearance), recombinant human DNase (dornase alfa) to reduce sputum viscosity, and bronchodilators as needed.
- Infection control: Prompt culture‑directed antibiotic therapy for pulmonary exacerbations; chronic suppressive inhaled antibiotics (e.g., tobramycin, aztreonam) for persistent Pseudomonas colonization; vigilant infection control to limit transmission of highly resistant organisms.
- CFTR modulators: Precision therapies target specific mutation classes. Ivacaftor is effective for gating mutations; combination modulators (lumacaftor/ivacaftor, tezacaftor/ivacaftor, and elexacaftor/tezacaftor/ivacaftor) substantially improve lung function, reduce exacerbations, and improve nutritional status in eligible genotypes.
- Nutritional support: Pancreatic enzyme replacement therapy (PERT) with meals/snacks, high‑calorie/high‑protein diets tailored to needs, fat‑soluble vitamin supplementation (A, D, E, K), and monitoring of growth parameters.
- Management of CFRD: Recognize as a unique entity—screen annually and manage primarily with insulin to improve outcomes.
- Surgery and advanced care: Consider sinus surgery for refractory disease, lobectomy or pneumonectomy selectively, and lung transplantation for end‑stage respiratory failure after multidisciplinary evaluation.
Monitoring and Follow-Up
Regular follow‑up in a specialized CF clinic is recommended with routine assessments: pulmonary function, sputum cultures, nutritional status, liver and pancreatic function, CFRD screening, and psychosocial support. Vaccination, including annual influenza and pneumococcal vaccination, is important.
Prognosis and Emerging Therapies
Prognosis has improved markedly with CFTR modulators, aggressive airway management, and nutritional optimization. New investigational approaches include gene therapy, mRNA therapy, and mutation‑agnostic correction strategies. Early diagnosis through newborn screening remains critical to optimize long‑term outcomes.
Clinical Pearls
- Always consider CF in infants with meconium ileus or failure to thrive, and in any patient with recurrent bronchiectasis and chronic productive cough.
- Genotype informs therapy—obtain CFTR mutation analysis early to evaluate modulator eligibility.
- Pancreatic enzyme dosing requires titration by weight, stool pattern, and nutritional goals; refer to dietitian experienced in CF care.
Resources
Refer patients and clinicians to national CF centers and registries for up‑to‑date treatment guidelines and access to specialized care and trials.
